This invention relates generally to compositions useful in preventing and treating human cytomegalovirus infection.
Cytomegalovirus (CMV) is one of a group of highly host specific herpes viruses that produce unique large cells bearing intranuclear inclusions. The envelope of the human cytomegalovirus (HCMV) is characterized by a major glycoprotein complex termed gB or gCI, which was previously referred to as gA.
Infection with HCMV is common and usually asymptomatic. However, the incidence and spectrum of disease in newborns and immunocompromised hosts establishes this virus as an important human pathogen. HCMV has also been suggested to be an important co-factor in the development of atherosclerosis and restenosis after angioplastic surgery.
Several HCMV vaccines have been developed or are in the process of development. Vaccines based on live attenuated strains of HCMV have been described. [See, e.g., S. A. Plotkin et al, Lancet, 1:528-30 (1984); S. A. Plotkin et al, J. Infect. Dis., 134:470-75 (1976); S. A. Plotkin et al, xe2x80x9cPrevention of Cytomegalovirus Disease by Towne Strain Live Attenuated Vaccinexe2x80x9d, in Birth Defects, Original Article Series, 20(1):271-287 (1984); J. P. Glazer et al, Ann. Intern. Med.; 91:676-83 (1979); and U.S. Pat. No. 3,959,466.] A proposed HCMV vaccine using a recombinant vaccinia virus expressing HCMV glycoprotein B has also been described. [See, e.g., Cranage, M. P. et al, EMBO J., 5:3057-3063 (1986).] However, vaccinia vaccines are considered possible causes of encephalitis. Other recombinant HCMV vaccines have been described. See, e.g., G. S. Marshall et al, J. Infect. Dis., 162:1177-1181 (1990); K. Berencsi et al, J. Gen. Virol., 74:2507-2512 (1993), which describe adenovirus-HCMV recombinants.
There remains a need in the art for additional compositions useful in preventing CMV infection by enhancing immune responses to HCMV vaccines and generating neutralizing antibody and/or cellular responses to CMV in the human immune system.
The present invention provides a series of DNA molecules expressing human cytomegalovirus (HCMV) genome fragments, which are particularly useful in inducing HCMV-specific immune responses.
Thus, in one aspect, the invention provides a DNA molecule which is non-replicating in mammals and which comprises at least one human cytomegalovirus antigen which is operably linked to regulatory sequences which express the antigen in the mammal. Advantageously, the antigen elicits an immune response in said mammal. In one preferred embodiment, the DNA molecule is a plasmid.
In another aspect, the invention provides a plasmid, pTet-gB, containing the portion of the HCMV genome (UL55) encoding gB. This plasmid further contains a tetracycline regulatable HCMV-immediate early promoter, which is useful in controlling expression of gB. Another plasmid of the invention encoding the full-length gB subunit protein is a pxcex94RC-gB plasmid.
Yet another plasmid of the invention, pxcex94RC-gB680, contains the portion of the HCMV genome encoding the N-terminal 680 amino acids of the gB protein (gB1-680).
The pxcex94RC-pp65 plasmid of the invention contains the portion of the HCMV genome (UL83) encoding the HCMV pp65 tegument protein. The pxcex94RC-pp150 plasmid contains the portion of the HCMV genome (UL32) encoding the HCMV pp150 tegument protein.
The pxcex94RC-exon-4 contains the portion of the HCMV genome (truncated UL123) encoding HCMV immediate-early (IE) exon-4.
In yet another aspect, the present invention provides an immunogenic composition of the invention comprising at least one of the DNA molecules of the invention and a carrier.
In still another aspect, the present invention provides a method of inducing HCMV-specific immune responses in an animal by administering to the animal an effective amount of an immunogenic composition of the invention. Preferably, this composition contains pxcex94RC-gB680, pTet-gB and/or pxcex94RC-pp65.
In yet a further aspect, the present invention provides a method of priming immune responses to a selected human cytomegalovirus immunogenic composition by administering an immunogenic composition of the invention prior to administration of the second immunogenic or vaccine composition.
Other aspects and advantages of the present invention are described further in the following detailed description of the preferred embodiments thereof.